Human Gene Module / Chromosome 3 / NLGN1

NLGN1neuroligin 1

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
8 / 17
Rare Variants / Common Variants
10 / 3
Aliases
NLGN1, KIAA1070,  MGC45115
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
3q26.31
Associated Disorders
ID
Relevance to Autism

In a genome-wide study, association was found between CNVs in the NLGN1 gene and autism in AGRE and ACC cohorts (European ancestry) (Glessner et al., 2009). In addition, a duplication of the NLGN1 gene was found in a patient with autism and mild intellectual disability (Leblond et al., 2012), and a rare mutation in NLGN1 has been identified in an individual with ASD (ORoak et al., 2012).

Molecular Function

This gene encodes a member of a family of neuronal cell surface proteins. Members of this family may act as splice site-specific ligands for beta-neurexins and may be involved in the formation and remodeling of central nervous system synapses.

Reports related to NLGN1 (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals. Kim J , et al. (2008) No -
2 Recent Recommendation LMO4 controls the balance between excitatory and inhibitory spinal V2 interneurons. Joshi K , et al. (2009) No -
3 Primary Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Glessner JT , et al. (2009) Yes -
4 Support Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. Leblond CS , et al. (2012) Yes ID
5 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
6 Recent Recommendation Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1. Gjrlund MD , et al. (2012) No -
7 Recent Recommendation Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number. Kwon HB , et al. (2012) No -
8 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
9 Support Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders. Nava C , et al. (2013) Yes ID
10 Recent Recommendation Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder. Sarachana T and Hu VW (2013) No -
11 Support Whole-genome sequencing of quartet families with autism spectrum disorder. Yuen RK , et al. (2015) Yes -
12 Positive association Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder. Kilaru V , et al. (2016) No -
13 Support Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes. Woodbury-Smith M , et al. (2017) Yes Macrocephaly
14 Recent recommendation Functional significance of rare neuroligin 1 variants found in autism. Nakanishi M , et al. (2017) Yes -
15 Highly Cited Neuroligin 1: a splice site-specific ligand for beta-neurexins. Ichtchenko K , et al. (1995) No -
16 Highly Cited Structures, alternative splicing, and neurexin binding of multiple neuroligins. Ichtchenko K , et al. (1996) No -
17 Highly Cited Binding of neuroligins to PSD-95. Irie M , et al. (1997) No -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Familial Maternal Simplex 22346768 Leblond CS , et al. (2012)
c.2383C>T p.His795Tyr missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Familial Paternal Unknown 23632794 Nava C , et al. (2013)
c.958G>A p.Val320Ile missense_variant De novo - Multiplex 25621899 Yuen RK , et al. (2015)
c.418G>T p.Asp140Tyr missense_variant Familial Paternal Simplex 28649445 Woodbury-Smith M , et al. (2017)
c.266C>T p.Pro89Leu missense_variant Familial Maternal Multi-generational 28841651 Nakanishi M , et al. (2017)
- p.Leu269Pro missense_variant Familial Paternal Simplex 28841651 Nakanishi M , et al. (2017)
- p.Gly297Glu missense_variant Familial Maternal Simplex 28841651 Nakanishi M , et al. (2017)
c.269C>T p.Thr90Ile missense_variant Unknown - Unknown 28841651 Nakanishi M , et al. (2017)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - copy_number_gain - - - 19404257 Glessner JT , et al. (2009)
c.494-62482T>G;c.554-55095T>G;c.494-55095T>G;c.37+59407T>G - intron_variant - - - 27219346 Kilaru V , et al. (2016)
c.647-21390T>C;c.767-21390T>C;c.707-21390T>C;c.191-21390T>C;c.-296-21390T>C;c.-269-21390T>C - intron_variant - - - 27219346 Kilaru V , et al. (2016)
SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Increased from 3 to 4.3 + acc

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2018
3
icon
4.3 + acc

Increased from 3 to 4.3 + acc

Description

3

7/1/2017
4
icon
3

Decreased from 4 to 3

Description

Glessner et al, 2009 found an overrepresentation of CNVs in the NLGN1 gene in ASD cases compared to controls (p=0.01). Ylisaukko-oja et al., 2005 found modest association of one marker in NLGN1 in a set of 100 Finnish families, but sequence analysis in 30 individuals revealed no mutations. A de novo missense variant in NLGN1 was identified in an ASD proband from the Simons Simplex Collection (O’Roak et al., 2012); this variant was later demonstrated in Nakanishi et al., 2017 to result in reduced intracellular protein levels in transfected COS7 cells and and impaired spine formation in transfected hippocampal neurons. Nakanishi et al., 2017 also characterized NLGN1 missense variants identified in additional ASD probands that resulted in altered cellular localization, reduced protein levels, and impaired spine formation, including a p.Pro89Leu missense variant that was observed in two siblings with ASD and their mother, who presented with OCD and anxiety disorder. Knock-in p.Pro89Leu mice displayed abnormal social behavior and impaired spatial memory.

4/1/2017
4
icon
4

Decreased from 4 to 4

Description

There is minimal evidence for the role of NLGN1 in autism. In one study (Glessner et al, 2009), investigators found an overrepresentation of CNVs in the NLGN1 gene in cases compared to controls (p=0.01). Ylisaukko-oja et al. found modest association of one marker in NLGN1 in a set of 100 Finnish families, but sequence analysis in 30 individuals revealed no mutations.

Reports Added
[Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Structures, alternative splicing, and neurexin binding of multiple neuroligins.1996] [Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals.2008] [Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.2012] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Neuroligin 1: a splice site-specific ligand for beta-neurexins.1995] [Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number.2012] [Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder.2016] [Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders.2013] [LMO4 controls the balance between excitatory and inhibitory spinal V2 interneurons.2009] [Binding of neuroligins to PSD-95.1997] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder.2013] [Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.2009]
4/1/2016
4
icon
4

Decreased from 4 to 4

Description

There is minimal evidence for the role of NLGN1 in autism. In one study (Glessner et al, 2009), investigators found an overrepresentation of CNVs in the NLGN1 gene in cases compared to controls (p=0.01). Ylisaukko-oja et al. found modest association of one marker in NLGN1 in a set of 100 Finnish families, but sequence analysis in 30 individuals revealed no mutations.

Reports Added
[Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Structures, alternative splicing, and neurexin binding of multiple neuroligins.1996] [Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals.2008] [Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder.2013] [Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.2012] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Neuroligin 1: a splice site-specific ligand for beta-neurexins.1995] [Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number.2012] [Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder.2016] [LMO4 controls the balance between excitatory and inhibitory spinal V2 interneurons.2009] [Binding of neuroligins to PSD-95.1997] [Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders.2013] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.2009]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

There is minimal evidence for the role of NLGN1 in autism. In one study (Glessner et al, 2009), investigators found an overrepresentation of CNVs in the NLGN1 gene in cases compared to controls (p=0.01). Ylisaukko-oja et al. found modest association of one marker in NLGN1 in a set of 100 Finnish families, but sequence analysis in 30 individuals revealed no mutations.

7/1/2014
No data
icon
4

Increased from No data to 4

Description

There is minimal evidence for the role of NLGN1 in autism. In one study (Glessner et al, 2009), investigators found an overrepresentation of CNVs in the NLGN1 gene in cases compared to controls (p=0.01). Ylisaukko-oja et al. found modest association of one marker in NLGN1 in a set of 100 Finnish families, but sequence analysis in 30 individuals revealed no mutations.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

There is minimal evidence for the role of NLGN1 in autism. In one study (Glessner et al, 2009), investigators found an overrepresentation of CNVs in the NLGN1 gene in cases compared to controls (p=0.01). Ylisaukko-oja et al. found modest association of one marker in NLGN1 in a set of 100 Finnish families, but sequence analysis in 30 individuals revealed no mutations.

Krishnan Probability Score

Score 0.60924462617799

Ranking 265/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.75579751197409

Ranking 4177/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.94785369860316

Ranking 17445/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 6

Ranking 264/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.093455342911078

Ranking 6271/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with NLGN1(1 CNVs)
3q26.31 17 Deletion-Duplication 27  /  517
Animal Models associated with NLGN1(10 Models)
NLGN1_1_KO_ HM 3 Genetic Mus musculus
NLGN1_2_Tg_HM 1 Genetic Mus musculus
NLGN1_3_Tg_HM 1 Genetic Mus musculus
NLGN1_4_KO_HM 1 Genetic Mus musculus
NLGN1_5_CKO_HM_NLGN2_NLGN3_CKO_HM 1 Genetic Mus musculus
NLGN1_5_CKO_HM_NLGN2_NLGN3_CKO_HM_Mature 1 Genetic Mus musculus
NLGN1_6_CKO_HM_NLGN3_CKO_HM 1 Genetic Mus musculus
NLGN1_7_CKO_HM 1 Genetic Mus musculus
NLGN1_8_KI_HM_P89L 1 Genetic Mus musculus
NLGN1_9_KI_HT_P89L 1 Genetic Mus musculus
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
B3GAT3 Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 3 Human Protein Binding 26229 O94766
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